Stress is associated with major depressive disorder (MDD), but the underlying mechanism remains elu-sive.However, some experiences, referred to as stress, may actually lead to resilience. It is thus criticalfirstto define what type of stress may lead to MDD. Long-term potentiation (LTP) and long-term depres-sion(LTD) are both sensitive to stress, but particularly to inescapable and not escapable stress. Thus, thesearethe psychological aspects of stress which contribute to the development of MDD, but by which mech-anismsremains still elusive. Interestingly, the same stress may facilitate LTD and impair LTP in the CA1region.In addition, repeated efforts are often required for learning under neutral conditions but single- orfewlearning trials are sufficient for forming stress-related memories. If LTP is crucial for normal learning, acombinationof limited LTP and facilitated LTD appears to have higher efficiency for storing stress-relatedmemories.Chronic psychological stress may cause a hyper-link among stress-related memories acrossthespatiotemporal due to shared quality of inescapability, leading to automatically negative appraisalthroughmemory generalization mechanisms in MDD patients when encountering new distinct eventswhichare perceived to share such similarity with previous experiences.